Certain cells in the body respond not only to chemical signals, but also to ions such as extracellular calcium ions (Ca.sup.2+). Changes in the concentration of extracellular Ca.sup.2+ (referred to herein as "[Ca.sup.2+ ]") alter the functional responses of these cells. One such specialized cell is the parathyroid cell which secretes parathyroid hormone (PTH). PTH is the principal endocrine factor regulating Ca.sup.2+ homeostasis in the blood and extracellular fluids.
PTH, by acting on bone and kidney cells, increases the level of Ca.sup.2+ in the blood. This increase in [Ca.sup.2+ ] then acts as a negative feedback signal, depressing PTH secretion. The reciprocal relationship between [Ca.sup.2+ ] and PTH secretion forms the essential mechanism maintaining bodily Ca.sup.2+ homeostasis.
Extracellular Ca.sup.2+ acts directly on parathyroid cells to regulate PTH secretion. The existence of a parathyroid cell surface protein which detects changes in [Ca.sup.2+ ] has been confirmed. Brown et al., 366 Nature 574, 1993. In parathyroid cells, this protein acts as a receptor for extracellular Ca.sup.2+ ("the calcium receptor"), and detects changes in [Ca.sup.2+ ] and to initiate a functional cellular response, PTH secretion.
Extracellular Ca.sup.2+ can exert effects on different cell functions, reviewed in Nemeth et al., 11 Cell Calcium 319, 1990. The role of extracellular Ca.sup.2+ in parafollicular (C-cells) and parathyroid cells is discussed in Nemeth, 11 Cell Calcium 323, 1990. These cells have been shown to express similar Ca.sup.2+ receptor. Brown et al., 366 Nature 574, 1993; Mithal et al., 9 Suppl. 1 J. Bone and Mineral Res. s282, 1994; Rogers et al., 9 Suppl. 1 J. Bone and Mineral Res. s409, 1994; Garrett et al., 9 Suppl. 1 J. Bone and Mineral Res. s409, 1994. The role of extracellular Ca.sup.2+ on bone osteoclasts is discussed by Zaidi, 10 Bioscience Reports 493, 1990. In addition keratinocytes, juxtaglomerular cells, trophoblasts, pancreatic beta cells and fat/adipose cells all respond to increases in extracellular calcium which likely reflects activation of calcium receptors of these cells.
The ability of various compounds to mimic extra-cellular Ca.sup.2+ in vitro is discussed by Nemeth et al., (spermine and spermidine) in "Calcium-Binding Proteins in Health and Disease," 1987, Academic Press, Inc., pp. 33-35; Brown et al., (e.g., neomycin) 128 Endocrinology 3047, 1991; Chen et al., (diltiazem and its analog, TA-3090) 5 J. Bone and Mineral Res. 581, 1990; and Zaidi et al., (verapamil) 167 Biochem. Biophys. Res. Commun. 807, 1990. Nemeth et al., PCT/US93/01642, International Publication Number WO 94/18959, and Nemeth et al., PCT/US92/07175, International Publication Number WO 93/04373, describe various compounds which can modulate the effect of an inorganic ion on a cell having an inorganic ion receptor, preferably modulate the effects of calcium on a calcium receptor.
The references provided in the background are not admitted to be prior art.